title: Efficient DNA binding and nuclear uptake by distamycin derivatives conjugated to octa-arginine sequences.
abstract: Efficient targeting of DNA by designed molecules requires not only careful fine-tuning of their DNA-recognition properties, but also appropriate cell internalization of the compounds so that they can reach the cell nucleus in a short period of time. Previous observations in our group on the relatively high affinity displayed by conjugates between distamycin derivatives and bZIP basic regions for A-rich DNA sites, led us to investigate whether the covalent attachment of a positively charged cell-penetrating peptide to a distamycin-like tripyrrole might yield high affinity DNA binders with improved cell internalization properties. Our work has led to the discovery of synthetic tripyrrole-octa-arginine conjugates that are capable of targeting specific DNA sites that contain A-rich tracts with low nanomolar affinity; they simultaneously exhibit excellent membrane and nuclear translocation properties in living HeLa cells.
authors.affiliation: Departamento de Química Orgánica, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Olalla
authors.initials: O
authors.lastname: Vázquez
authors.forename: Juan B
authors.initials: JB
authors.lastname: Blanco-Canosa
authors.forename: M Eugenio
authors.initials: ME
authors.lastname: Vázquez
authors.forename: Jose
authors.initials: J
authors.lastname: Martínez-Costas
authors.forename: Luis
authors.initials: L
authors.lastname: Castedo
authors.forename: José L
authors.initials: JL
authors.lastname: Mascareñas
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004214:Distamycins / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000970:Antineoplastic Agents; D004214:Distamycins; D009842:Oligopeptides; D011758:Pyrroles; C500307:octa-arginine peptide; D004247:DNA